title: Biodegradable star HPMA polymer conjugates of doxorubicin for passive tumor targeting.
abstract: New biodegradable star polymer-doxorubicin (Dox) conjugates designed for passive tumor targeting were investigated and the present study described their synthesis, physico-chemical characterization, drug release and biodegradation. In the conjugates the core formed by poly(amido amine) (PAMAM) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers bearing doxorubicin attached by hydrazone bonds, which enabled intracellular pH-controlled drug release, or by a GFLG sequence, which was susceptible to enzymatic degradation. The controlled synthesis utilizing semitelechelic copolymer precursors facilitated preparation of biodegradable polymer conjugates in a broad range of molecular weights (110-295 kDa) while still maintaining low polydispersity (∼1.7). The polymer grafts were attached to the dendrimers either through stable amide bonds or enzymatically or reductively degradable spacers, which enabled intracellular degradation of the high molecular weight polymer carrier to products that were able to be excreted from the body by glomerular filtration. Biodegradability tests showed that the rate of degradation was much faster for reductively degradable conjugates (completed within 4 h) than the degradation of conjugates linked via an enzymatically degradable oligopeptide GFLG sequence (within 72 h). This finding was likely due to the difference in steric hindrance for the small molecule glutathione and the enzyme cathepsin B. As for drug release, the conjugates were fairly stable in buffer at pH 7.4 (model of blood stream) but released doxorubicin either under mild acidic conditions or in the presence of lysosomal enzyme cathepsin B, both of which modeled the tumor cell microenvironment.
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, v.v.i., Heyrovský Sq. 2, 162 06 Prague 6, Czech Republic. etrych@imc.cas.cz
authors.forename: Tomáš
authors.initials: T
authors.lastname: Etrych
authors.forename: Jiří
authors.initials: J
authors.lastname: Strohalm
authors.forename: Petr
authors.initials: P
authors.lastname: Chytil
authors.forename: Peter
authors.initials: P
authors.lastname: Černoch
authors.forename: Larisa
authors.initials: L
authors.lastname: Starovoytova
authors.forename: Michal
authors.initials: M
authors.lastname: Pechar
authors.forename: Karel
authors.initials: K
authors.lastname: Ulbrich
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D001672:Biocompatible Materials / Q000138:chemical synthesis / Q000737:chemistry*; D050091:Dendrimers / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D004355:Drug Stability; D008689:Methacrylates / Q000737:chemistry*; D015394:Molecular Structure; D012995:Solubility
chemical_list: D000903:Antibiotics, Antineoplastic; D001672:Biocompatible Materials; D050091:Dendrimers; D004337:Drug Carriers; D008689:Methacrylates; C104700:PAMAM Starburst; D004317:Doxorubicin; C032802:hydroxypropyl methacrylate